Archive for the ‘"bird" flu’ Category

The Center for Disease Control and Prevention, AKA the CDC, America's central medical laboratory has recently had multiple problematic episodes. I was trying to follow up on the vials of smallpox virus that were found in an old refrigerator that the FDA apparently had forgotten, The question, of course, was whether the virus samples were long dead or still viable. They had been sent to the CDC to have that highly significant issue resolved.

Since then there has been a followup announcement, but also several articles on significant issues with procedures and safety at the CDC itself. The first was published in The New York Times, AKA NYT, (as well as in other papers, but I get the NYT daily on my iPad , so saw it there first). The startling title was "C.D.C. Closes Anthrax and Flu Labs after Accidents." The current director of the CDC, Dr. Thomas Frieden, called the lab/agency "the reference laboratory to the world," but admitted there had been a series of accidents (actually lapses in set safety procedures), in the recent past, that were quite frightening.

A month ago potentially infectious samples of anthrax, a bacteria found naturally in soil and commonly affecting wild and domesticated animals worldwide, causing an extremely serious, but rare illness in people, were sent to labs that were not equipped to deal with them (anthrax would normally be handled only with the highest level of protective biosafety gear and procedures (BSL-4). The CDC also has a rather simplistic YouTube video discussing anthrax's use as a potential bioterrorism weapon, but in this case 62 or more CDC employees were potentially exposed to the bacteria in the course of their work.

The good news is it appeared nobody was in danger; all those employees were given the anthrax vaccine and also begun on antibiotics. The background information available online says there has never been person to person spread of the disease.

It appears that it's exceedingly tough to get rid of anthrax in the environment; I'll go over the classic historical example of how careful government researchers have been with its spores..

In the 1940s, British scientists used a small Scottish island (Gruinard) for germ warfare research. That island, thoroughly contaminated with anthrax spores, remained off-limits for forty+ years before extraordinary efforts, begun in 1986, rendered it safe for ordinary use. The surface of the island was only 484 acres; it was sprayed with a herbicide, then all dead vegetation was burned off. Next 200 tons of formaldehyde solution was diluted in 2,000 tons of seawater and sprayed over the entire island. Perforated tubing was used to ensure that 50 liters of solution were applied to every square meter being treated.

Later the effectiveness of the decontamination process was assessed by taking two duplicate sets of soil samples. Each was tested at two major government labs. Anthrax spores were detected only in "small quantities in a few places." These specific areas were treated in July 1987, followed by further soil sampling in October 1987. No further traces of anthrax spores were found.

Blood samples from local rabbits were also tested for anthrax antibodies. No such antibodies were found.

Following these measures, a farmer grazed part of his flock of sheep on the island for six months. The sheep were inspected monthly by the District Veterinary Officer, and returned to the mainland in October 1987 in excellent condition.

On April 24, 1990, 4 years after the decontamination works had been completed, a Defense Minister visited the island and removed the safety signs, indicating that the island had finally been rendered safe. Then, per agreement the island was sold back to the heirs of the original owner for the WWII sale price of £500.

But a senior British archeologist said he still wouldn't set foot on the island; he was concerned because of potentially infectious particles found in some of his digs.

Yet another NYT piece, "Ticking Viral Bombs, Left in Boxes," this one written by a distinguished physician, Lawrence K. Altman, M.D. recalls the irony of the outcry for mass smallpox vaccination of our entire U.S. population after 9-11 (when no Iraqi supply of the deadly bacterium was ever located), contrasted with the recent finding of six vials, two with live smallpox bugs, being found in in Bethesda, almost within "spitting distance" of our center of government.

In 2011 the Birmingham Mail reviewed a tragic lab accident which led to the last known smallpox death . The city, now England's second largest, was a site of a medical research laboratory associated with the local medical school. Viral particles got into an air duct and a photographer whose studio was one story up from the lab became the last known case of active smallpox and died from the disease in spite of having been vaccinated twelve years before

Dr. Altman discusses the pros and cons of eradicating the last two known stocks of the virus, one at the CDC, the other in a Russian lab in Siberia. Even if the natural virus is finally and totally eliminated , a rogue group may well be able to re-establish their own supply from the known genetic sequence of smallpox.

Lastly I saw a NYT article with an even more disturbing title, "After Lapses, C.D.C. Admits a Lax Culture at Labs." CDC workers had somehow shipped a dangerous strain of avian influenza to a poultry research lab run by the Department of Agriculture. Known as H5N1, the virus had killed more than half of the 650 people who had been infected with it since 2003. Again there were no deaths from this mistake.

After all of this recent furor plus the historical examples, I'm heartily in favor of the idea that's been broached saying such dangerous organisms should be confined to a minimal number of labs and even those clearly need to tighten up their standards.

So how do you re-create a virus? Or at least understand how it did what it did?

In the previous post I brought us up to 1995 when Jeffery K Taubenberger, who had received a combined MD/PhD degree at the Medical College of Virginia in 1986-87, and then went to the National Cancer Institute for pathology training, got interested in the 1918-1919 influenza virus. He used the technique known as polymerase chain reaction (PCR ) which allows a researcher to make many copies of a short segment of DNA inexpensively (If you click on the link you can experience PCR yourself). It was invented by a scientist named Kary Mullis who won a Nobel Prize in 1993 for his novel approach to genetic information.

Taubenberger and his associates went to the National Tissue Repository (NTP) and found 70 of the 100 autopsy files from the pandemic had tissue samples; 13 of these seemed candidates for recovering RNA and two actually yielded suitable RNA fragments. Data from the first case showed the virus was an H1N1 subtype and the second NTP tissue plus that obtained by Hultin in Alaska enabled the next nine years of the project, sequencing the genome of the virus.

The process is described in the Human Genome Project Information (HGP) packet online, but in brief the genetic material is broken into small chunks, each of which is used as a template, a model to be copied. Those models allow the research team to make duplicate fragments that have slight differences in which chemical bases (with abbreviations A, T, C, and G for DNA and U substituting for T in RNA) are present. Other steps, many of which are now automated, allow the re-creation of the sequence, the pattern, of the bases. In 2006 the HGP group finished enormous task of mapping the DNA sequence for all 24 human chromosomes.

In the meantime Taubenberger and his colleagues had moved into the field of reverse genetics technology, trying to find out what physical characteristics (the scientific term is phenotype) are due to a particular gene, by slightly altering the gene's structure. Their 2007 paper, available in PubMed Central, a free digital database of full-text scientific literature in biomedical and life sciences, describes their efforts to sequence the entire genome (all of the biological information needed to build and maintain a living example of that organism) of the 1918-1919 influenza virus.

Then they could perform actual experiments with viruses that had at least one of the 1918 flu virus genes. They were very careful with this work; their research was performed two labs that had been through the laborious certification process as BioSafety Level 3 or higher. The new viruses that had all eight genes from the 1918 flu were considerably more damaging, in animals at least, than those that had less than the full complement of genes.

Their conclusions, at this point, were fascinating: the 1918 virus was likely brand new, at least to mankind and came from an avian source, but which bird was involved is unknown. They haven't been able to determine yet exactly why the human infection was so deadly.

It could be a deadlier version of this one

They think we're at a mid-point in understanding the worst flu pandemic and we clearly need to learn more about it.

Why? Because other influenza virus mutations will eventually be coming our way.

There's been a recent controversy as to whether potentially dangerous medical information should be made available to the public. Now it's happened and I'm somewhat less concerned than I was a few weeks ago. The online version of Nature just published the work of the University of Wisconsin group on making the Highly Pathogenic Avian Influenza (HPAI) type A H5N1 virus transmissible from mammal to mammal, in this case ferrets.

This is potentially a terrible disease; it's killed 355 of the 602 humans (~59%) known to have contracted the HPAI A(H5N1) virus to date. None of those cases involved human to human spread of the flu bug involved. But that's roughly 600 times as lethal as an "ordinary" flu pandemic and more than 20 times as deadly as the 1918 flu.

So why am I less worried than I was?

When I read the article in Nature in detail (and it's tough slogging even for a physician), I realized that the virus, in the process of making it capable of airborne transmission, had also been made less virulent. None of the ferrets used as research subjects died of the disease . The new virus was also found to be preventable by a vaccine and treatable with one of the existing anti-flu medications.

The other thing I quickly understood is this is not a process that the average man (or woman) on the street or even the vast majority of scientists and/or physicians could duplicate. It involved an enormously complex set of laboratory procedures, many of which would demand long-term expertise and experience in the field. Theoretically a virology lab could be influenced by links to a terrorist group or have their own "ultra-green" agenda; neither possibility sounds at all likely to me.

The other paper, detailing the work done on HPAI A(H5N1) in Rotterdam, is yet to be published. That one has me more concerned, but I've just read a paper "Dangerous for ferrets: lethal for humans?" that carefully explores the question involved.

The authors reminded us that a previous paper had discussed the recreation of the so-called Spanish flu virus that killed 50 million worldwide in 1918. I'll write about that in detail some other time, but when that publication appeared, its authors were hailed as heroes, not as dolts.

The work of Ron Fouchier, a senior figure at the Erasmus Medical Center in Holland took the virology world by storm. He first announced his group's alteration of H5N1 at an international meeting in Malta in September, 2011. Initially his variant of the flu virus was thought to be much more deadly to ferrets than the UW bug. A May 3, 2012 paper in Time Healthland discusses the infighting among scientists that followed, but notes that Fouchier's paper should be out in the magazine Science in the near future.

Apparently Fouchier's mutated virus also turned out to be less of a ferret-killer than was initially thought.

There's the normal flu season and the other kind

But that's not the major issue here. Most of those working in the virology field feel a natural mutation of H5N1 or H1N1 or other flu strains is more to be feared than anything produced in a lab. Yet the relatively benign 1977 H1N1 flu pandemic, so-called Russian flu, may have escaped from deep freeze in a lab.

Shortly after I wrote my post on the dangers of H5N1 HPAI, my weekly copy of JAMA, AKA the Journal of the American Medical Association, arrived containing a commentary titled "International Debate Erupts over Research on Potentially Dangerous Flu Strains." The pros and cons of release of the two groups' research were discussed and the rationale for publishing the methods and details was explained.

One expert in the field had a balanced view. He felt release of the details of the recent research on H5N1 HPAI might be extremely useful to those who evaluate which strains of influenza are about to pose a real threat to humans and could potentially cause epidemics. Doing so might provide lead time for other scientists who work on vaccines to prevent wider spread of the particular strain of flu.

But in a January, 2012 online discussion of the controversy the head of a university Center for Biosecurity felt the lives of hundreds of millions of people could be at risk if such an engineered virus strain were to be released, even accidentally. He feels that continued research would require the level of biosecurity utilized with other dire agents such as smallpox.

The first infectious disease specialist countered with the concept that H5N1 HPAI wasn't an especially likely pick for those interested in bioterroism. It's certainly not a selective weapon and its use would require considerable expertise.

The second expert noted there had been no data that such a strain of flu would ever develop naturally, outside the lab, and we had to return to the concept of weighing potential harm versus good.

Now the original researchers have stated that the new viral subtype isn't as deadly as feared; it hasn't killed the ferrets being used as laboratory substitutes for humans and has proven to be controllable with vaccines and antiviral medications. Because of ethical limitations it hasn't been tried on human subjects and they don't know whether it even could be spread among humans.

And which of these is the worst?

I think we're treading very close to the edge here. I don't look forward to widespread beneficial effects of complete publication of the ongoing lab research results. And I do fear the possibility of groups who don't care if they kill off a third of everyone, including their own followers. Accidental release of a lab-engineered organism into the human population could also happen, even if unlikely.

Another online article said the work on the mutant form of H5N1 had been performed in BS-3 labs, used for studying agents that can cause serious or lethal disease, but do not ordinarily spread among humans and have existing preventives or treatments.

A GAO 2009 report counted 400 accidents at BS-3 labs in the previous decade. Scientists argued that the H5N1 HPAI studies must be moved to BS-4 labs with one professor stating, "An escape would still produce the worst pandemic in history." Yet between 1978 and 1999, over 1,200 people acquired deadly microbes from BS-4 laboratories, the biosafety-4 level facilities that normally deal with infectious agents that have no known preventive measures or treatment.

Scandia National Laboratory's International Biological Threat Reduction program directed by Ren Salerno has a worldwide ongoing effort to prevent laboratory accidents, but there are varying standards for biosafety and at least 18 BS-4 labs outside of the US as of 2011.

I just looked at the World Health Organization's (WHO) most recent statistics on human cases of avian influenza H5N1, the dreaded bird flu. These cover the period from 2003 through March 10, 2012 and report 596 total cases and 350 deaths. The counties with the great numbers of cases are Indonesia, Egypt and Vietnam and I didn't see any reports of bird flu infections in the Western Hemisphere...yet.

That's a relatively tiny number of cases, but an incredibly high percentage of deaths, nearly 60% of those infected. But influenza epidemics and pandemics have been a common occurrence in the last century. So what's the difference between our seasonal flu, the pandemics and this new flu?

The Food and Agriculture Organization of WHO has published the first three chapters (of nine) of an online primer on avian influenza. It seemed a good place for me to start.

The first issue is how easily a new flu virus passes from animals to humans (the usual hosts are birds, typically ducks and, secondarily, chickens, especially if flocks are raised in proximity to each other and the ducks are "free range") and then from one person to another. The second is how deadly the particular influenza virus is.

Up until now those infected with the relatively new H5N1 subtype, sometimes called H5N1 HPAI, have had direct or at least indirect contact with infected birds. The HPAI is the acronym for "Highly Pathogenic Avian Influenza," but in this case highly pathogenic, which translates into very likely to cause disease, mostly refers to birds. Unlike seasonal flu, there's been (thus far) absolutely no documented human-to-human spread of the virus.

The 1918 Spanish flu infected 1/3 of everyone alive and killed at least 20 million. My math says that's roughly 4%, but 3% is the usual quoted figure. Seasonal flu kills less than 0.1% of those infected. So this flu, if it does reach a human, is terrible.

These experiment may prove deadly

Recently there has been an enormous flap about the work done in two laboratories. I had heard about the issue, but hadn't read the details until my monthly copy of On Wisconsin arrived and I realized one of the labs was in Madison. CNN has an online review of the problem. The researchers wondered why this deadly flu variety hasn't spread from person to person, so they created a mutated form that could be easily transmitted from one mammal to another using ferrets as their test animal.

Then the excrement collided with the rotating blades. Detailed papers were about to be published in prominent, widely read journals, Nature and Science. The National Science Advisory Board for Biosecurity temporarily stopped the process, saying the papers should be published without methods or details to stop terrorists from making their own highly lethal and easily spread virus strains.

Think about it; if this virus subtype gets released it could potentially infect a third or perhaps all of all of us now alive and kill 60% of those whom it strikes. We have a world population of roughly 7 billion now, so that's somewhere between 1.4 and 4.2 billion deaths.

Yet many in the scientist community seems to think all the details of the research should be given to those responsible groups that need help with H5N1 HPAI.

Two days ago I began a post on zoonoses, diseases that spread from animals to humans. As usual, my interest led me from one fairly-limited topic to more-generalized subjects and I eventually decide to write a multi-post discussion of viral diseases that either have caused massive, widespread epidemics (AKA pandemics) or could potentially lead to them.

The number of deaths they have resulted in is staggering. HIV/AIDS has killed over 25 million of us in the past 30 years; the Black Plague over a 330-year period killed 75 million and smallpox is estimated to have caused over 300 million deaths over the centuries.

But let's start with influenza, the virus that we read about year after year as a worldwide threat. In the fall my wife and I get flu shots; we got used to doing so when we were both on active duty as Air Force medical staff personnel. It was routine; I didn't pay a lot of attention to what this year's shot contained and only vaguely kept up with anything written about the flu itself.

Then so-called "bird flu" came along and the world geared up for a terrible pandemic.Usually the kind of influenza virus found in birds doesn't infect humans. But one unusual strain, called H5N1 (I'll explain what that means later) killed a six-year-old boy in Thailand in 2003. Of the people who caught this virus, 60 % died.

Most of us have heard about the Spanish flu, a major pandemic that infected a third of everyone living in 1918-1919 and caused 20 to 40 million deaths worldwide. Yet only 3% of those whom the virus infected died from it.

The so-called Asian flu pandemic in 1956-1958 causes 2 million deaths; the Hong Kong flu in 1968-1969 killed 1 million and the yearly seasonal flu results in anywhere from 5 to 15% of us getting ill; 250,000 to 500,000 die as a result. But these flu strains actually only resulted in a death ratio of less than 0.1%.

As it turned out, there was very little person to person spread of the avian flu. If there had been the results could have been catastrophic.

But the pigs had nothing to worry about; we did!

One of the outcomes of the avian H5N1 outbreak was fortuitous. When the "Swine flu" pandemic occurred in 2009-2010, the public health establishment and the medical community were considerably better prepared. The CDC summary is worth reading as it documents the steps taken to contain the virus; actually this was a flu strain that was transmitted from person to person and wasn't present in US pig herds.

The virus itself had genes from four different influenza virus sources, two from pigs, one from birds and one from a human flu virus. The CDC widely distributed kits to labs enabling them to identify the new viral strain. They and the World Health Organization (WHO) kept tabs on the numbers of cases of the new disease and WHO announced a global pandemic in June, 2009 .

A vaccine was developed with unusual speed and a preliminary target group of higher-risk individuals was identified; this consisted of 159 million people in the US. Vaccine safety was tested in various groups and the vaccine itself was administered starting in early October; by late December 2009 enough had been produced to allow vaccination of anyone wishing it.

The final results were impressive; less than two-thirds of a million people caught the virus and the death rate was 0.03%